GWAS Studies Identify Loci Associated with Chronic Hepatitis B Infection
Hepatitis B is a disease caused by the partially double stranded DNA hepatitis B virus. The virus infects the liver causing an acute infection characterized by inflammation of the liver, jaundice, vomiting, nausea among other symptoms. The infection may become chronic in some individuals which leads to cirrhosis and liver cancer. Transmission occurs through exposure to infectious blood or body fluids containing blood and can be passed on from mother to child. Hepatitis B is prevalent in many areas worldwide and is endemic in China. It is clear from previous studies that some individuals are more susceptible to chronic infection while others can more easily clear the infection. Several GWAS studies have been conducted which have determined some risk loci to chronic infection. A 2013 study done on the Han Chinese population revealed two new loci for hepatitis B infection. 1 2013 GWAS Study A 3-phase GWAS study was performed on 951 HBV carriers and 937 control subjects from Shanghai or a suburb of Shanghai, Zhangjiagang. The first phase was the initial genome wide association study which included these subjects. Two replications were done afterwards. Replication 1-a included 1248 HBV carriers and 1248 controls from southern Jiangsu and 1-b included 1000 HBV carriers and 1803 controls from Jiangsu. Replication 2-a had 981 HBV carriers and 1417 controls from southern China and 2-b had 1001 HBV carrier and 1205 controls from northern China. Whole blood was taken for genomic DNA in all cases. SNP chips were used for genotying. HBV carriers were genotyped using Illumina Human Omni Express 12vI chips and controls were genotyped with OmniZhongHua chips. Replication genotyping was done with Sequenom Iplex platform and Applied Biosystems Taqman assay on 1-a and 1-b, 2-a and 2-b respectively. 2 The study identified two HLA SNPs which are associated with chronic hepatitis B infection. In brief, HLA stands for human leukocyte antigen and the gene loci is located on chromosome 6. These genes encode for MHC Class I and Class II which present antigen to T cells. Class I MHC molecules are located on all nucleated cells and present and stimulate cytotoxic T cells and MHC Class II are presented on specialized antigen presenting cells and stimulate helper T cells. MHC Class I has three major genes known as HLA-A, HLA-B and HLA-C. MHC Class II has three major genes as well, known as HLA-DP, HLA-DQ and HLA-DR. There are also several classes of minor genes in both MHC Class I and II. The HLA gene loci are also among the most variable among populations. The six loci have over a 100 detected alleles in the human population. 3 In the current study they discuss how they validated that the A allele (HLA-A) rs3077 and rs9277535 and the G allele rs2856718 were associated with less risk for chronic hepatitis B. These SNPs were associated with expression of HLA-DPA1 and HLA-DPB1. These genes code for cell surface receptors which activate CD4 T cells consistent with a role they may play in the clearance of infection. They also discovered two new SNPs associated with chronic hepatitis infection. The first SNP, was near HLA-C at position 6p21.33 and the second was near the UBE2L3 gene at 22q11.21. HLA-C codes for Type I HLA molecule responsible for stimulating cytotoxic T cells and UBE2L3 is a ubiquitin conjugating enzyme which may accelerate degradation of NFKB transcription factor important for establishing an immune response. Together these SNPs may provide insight into genetic modifications that correlate with the ability to clear infection. 2 References 1. http://en.wikipedia.org/wiki/Hepatitis_B 2. Zhibin, H. ''et. al. ''New loci associated with chronic hepatitis B virus infection in Han Chinese. Nature Genetics (2013) doi:10.1038/ng.2809. http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2809.html 3. http://en.wikipedia.org/wiki/Human_leukocyte_antigen